Review and meta‐analysis of systematic searches for uniparental disomy (UPD) other than UPD 15

All systematic searches for uniparental disomy (UPD) so far published and comprising clinically defined populations (Silver‐Russell syndrome/primordial growth retardation (SRS/PGR) (n = 14), multiple malformations (n = 2), or rare syndromes (n = 12)) or situations at risk (confined placental mosaicism (CPM) (n = 13), spontaneous abortions (n = 6), additional marker chromosomes (n = 15), balanced non‐Robertsonian translocations (n = 3), or balanced Robertsonian translocations (n = 15)) were reviewed. In many studies clinical and/or cytogenetic information on fluorescent in situ hybridization (FISH) results was very scarce. Meta‐analysis concerning an adequate number of cases was possible for SRS/PGR, CPM, additional marker chromosomes, and balanced Robertsonian translocations only. As expected, the highest risk for UPD was found in cases with translocations between homologous acrocentric chromosomes (11 cases with UPD of 15 investigated) and in CPM due to a meiotic error (25 of 51 cases). In prenatal investigations or in cases with a normal phenotype, translocations between nonhomologous acrocentric chromosomes implied a risk for UPD of less than 0.5%. The risks for maternal UPD 7 in cases with SRS/PGR, for UPD 15 in cases with an additional inv dup(15) marker chromosome, and for UPD of any chromosome in cases with multiple malformation/mental retardation were approximately 5.5%, and approximately 1.3%, respectively. Searches for UPD in well‐defined syndromes (Brachmann‐De Lange syndrome, Sotos syndrome, Rett syndrome, Weaver syndrome, or XX true hermaphroditism) were disappointing. Not a single case was found. © 2002 Wiley‐Liss, Inc.     

Identification of uniparental disomy in phenotypically abnormal carriers of isochromosomes or Robertsonian translocations

Carriers of either homologous or non-homologous acrocentric rearrangements are at an increased risk for aneuploidy, and, thus, for uniparental disomy (UPD). Abnormal phenotypes due to genomic imprinting are associated with UPD for the acrocentric chromosomes 14 and 15. The purpose of this study was to determine the prevalence of UPD in a population with acrocentric rearrangements (either an isochromosome or a Robertsonian translocation) and abnormal phenotypes. Fifty individuals were studied. Of the 50 rearrangements, two were homologous rearrangements and both showed UPD. Forty-eight were non-homologous Robertsonian translocations, of which two showed UPD. This study demonstrates that UPD explains the abnormal phenotypes in some balanced carriers of acrocentric rearrangements. Our results and the large number of case reports in the literature suggest that patients with abnormal phenotypes and acrocentric rearrangements of chromosomes 14 or 15 should be tested for UPD.     

No evidence of uniparental disomy 2, 6, 14, 16, 20, and 22 as a major cause of intrauterine growth retardation

Intrauterine growth retardation (IUGR) is defined as length and/or weight below the 10th percentile. Etiology and, consequently, long-term outcome are extremely heterogeneous with chromosomal abnormalities found in up to 7%. Recently, uniparental disomy (UPD), i.e. the inheritance of both homologues of one pair of chromosomes from only one parent, was found in an increasing number of children with IUGR. Particularly, UPD of chromosome 7 was found in up to 10% of patients with IUGR and/or a phenotype of primordial growth retardation or Silver-Russell syndrome (SRS), but also UPD of chromosomes 2, 6, 14, 16, 20, and 22 was reported in single cases with IUGR. To evaluate impact and relevance of UPD in children with IUGR we investigated 23 sporadic cases with IUGR subsequently diagnosed as primordial growth retardation (n = 13) or SRS (n = 10) by molecular methods for UPD of chromosomes 2, 6, 14, 16, 20, and 22. No instance of UPD was found. Inheritance of all chromosomes investigated was biparental in all cases. Therefore, we conclude that UPD of these chromosomes is not a major cause of IUGR.     

Complex and segmental uniparental disomy (UPD): review and lessons from rare chromosomal complements

OBJECTIVE—To review all cases with segmental and/or complex uniparental disomy (UPD), to study aetiology and mechanisms of formation, and to draw conclusions.
DESIGN—Searching published reports in Medline.
RESULTS—The survey found at least nine cases with segmental UPD and a normal karyotype, 22 cases with UPD of a whole chromosome and a simple or a non-homologous Robertsonian translocation, eight cases with UPD and two isochromosomes, one of the short arm and one of the long arm of a non-acrocentric chromosome, 39 cases with UPD and an isochromosome of the long arm of two homologous acrocentric chromosomes, one case of UPD and an isochromosome 8 associated with a homozygous del(8)(p23.3pter), and 21 cases with UPD of a whole or parts of a chromosome associated with a complex karyotype. Segmental UPD is formed by somatic recombination (isodisomy) or by trisomy rescue. In the latter mechanism, a meiosis I error is associated with meiotic recombination and an additional somatic exchange between two non-uniparental chromatids. Subsequently, the chromatid that originated from the disomic gamete is lost (iso- and heterodisomy). In cases of UPD associated with one isochromosome of the short arm and one isochromosome of the long arm of a non-acrocentric chromosome and in cases of UPD associated with a true isochromosome of an acrocentric chromosome, mitotic complementation is assumed. This term describes the formation by misdivision at the centromere during an early mitosis of a monosomic zygote. In cases of UPD associated with an additional marker chromosome, either mitotic formation of the marker chromosome in a trisomic zygote or fertilisation of a gamete with a marker chromosome formed in meiosis by a disomic gamete or by a normal gamete and subsequent duplication are possible.
CONCLUSIONS—Research in the field of segmental and/or complex UPD may help to explain undiagnosed non-Mendelian disorders, to recognise hotspots for meiotic and mitotic recombinations, and to show that chromosomal segregation is more complex than previously thought. It may also be helpful to map autosomal recessively inherited genes, genes/regions of genomic imprinting, and dysmorphic phenotypes. Last but not least it would improve genetic counselling.


Keywords: genomic imprinting; isochromosome; Robertsonian translocation; uniparental disomy (UPD)     

Robertson-Translokationen und uniparentale Disomien: Indikationen zur pränatalen Diagnostik?

Uniparental disomy (UPD) is defined by the inheritance of both homologue chromosomes/chromosomal regions of a pair from only one parent resulting in an imbalance of the expression of imprinted genes. With the recent identification of several diseases associated with UPD, the diagnostic significance of this molecular finding has become a focus of interest. While the clinical consequence of UPD of chromosome 15 is well established (Prader-Willi and Angelman syndromes), the association between UPD and further clinical entities such as Silver-Russell syndrome or transient neonatal diabetes mellitus could recently be delineated. In particular, acrocentric chromosomes are prone to be affected by malsegregation events possibly resulting in UPD: these chromosomes are involved in Robertsonian translocation (RT) formation. Apart from UPD15, UPD14 results in defined syndromes. Therefore, the demand for prenatal testing of UPD14 and UPD15 has increased for cases of a prenatally detected RT or of a RT carrier. In the following, the significance and consequences of these testing approaches will be discussed.     

A child with Angelman syndrome and trisomy 13 findings due to associated paternal UPD 15 and segmental UPD 13

A child with Angelman syndrome, cutis aplasia, cleft palate, and congenital microform cleft lip, born to a father with a Robertsonian translocation 13;15 is described. Molecular studies using polymorphic markers on chromosomes 15 and 13 showed paternal uniparental disomy (UPD) 15 and segmental UPD 13.     

Identification of interstitial maternal uniparental disomy (UPD) (14) and complete maternal UPD(20) in a cohort of growth retarded patients

The association of uniparental disomy (UPD) and short stature has been reported for different chromosomes and in several conditions. Therefore, we investigated a cohort of 21 patients referred because of intrauterine and postnatal growth retardation for UPD of chromosomes 2, 7, 9, 14, 16, and 20. Typing of short tandem repeats showed maternal UPD(14) and maternal UPD(20) in two cases. In the first case, an interstitial UPD(14) was detected and the growth retarded newborn showed some additional clinical signs in common with the putative "maternal UPD(14) syndrome". The maternal UPD(20) patient showed minor features. However, since it is only the second maternal UPD(20) case it is too early to delineate a specific syndrome and the role of this constitution in growth remains to be investigated. Our data suggest that searching for UPD in growth retarded patients is a helpful approach to getting more information on the role of UPD in growth retardation. Based on our results, general considerations and indications for UPD testing are discussed.


Keywords: uniparental disomy 14; uniparental disomy 20; growth retardation; Silver-Russell syndrome     

Is maternal duplication of 11p15 associated with Silver-Russell syndrome?

Background: Silver-Russell syndrome (SRS) is a heterogeneous malformation syndrome characterised by intrauterine and postnatal growth retardation (IUGR, PGR) and dysmorphisms. The basic causes are unknown, however in approximately 10% of patients a maternal uniparental disomy (UPD) of chromosome 7 or chromosomal aberrations can be detected. Four growth retarded children, two with SRS-like features, associated with maternal duplications of 11p15 have been described. Considering the involvement of this genomic region in Beckwith-Wiedemann overgrowth syndrome (BWS), we postulated that some cases of SRS—with an opposite phenotype to BWS—might also be caused by genomic disturbances in 11p15.

Methods: A total of 46 SRS patients were screened for genomic rearrangements in 11p15 by STR typing and FISH analysis.

Results: Two SRS patients with duplications of maternal 11p material in our study population (n = 46) were detected. In patient SR46, the duplicated region covered at least 9 Mb; FISH analysis revealed a translocation of 11p15 onto 10q. In patient SR90, additional 11p15 material (approximately 5 Mb) was translocated to the short arm of chromosome 15.

Conclusions: We suggest that diagnostic testing for duplication in 11p15 should be offered to patients with severe IUGR and PGR with clinical signs reminiscent of SRS. SRS is a genetically heterogeneous condition and patients with a maternal duplication of 11p15.5 may form an important subgroup.

     

Sperm segregation analysis of a (13;22) Robertsonian translocation carrier by FISH: a comparison of locus-specific probe and whole chromosome painting

BACKGROUND: The t(13;22) Robertsonian translocation constitutes a rare form of rearrangement between acrocentric human chromosomes. Most of the meiotic segregation studies of human Robertsonian translocations have been performed on common t(13;14) and t(14;21) translocations. Analysis of the chromosomal constitution in sperm of Robertsonian translocation carriers is of great interest for assessing the risk of unbalanced forms and adapting genetic counselling. In the present study, we present the first meiotic segregation study of a t(13;22) Robertsonian translocation in human sperm. METHODS: A total of 11 787 sperm nuclei were scored using two distinct FISH labelling techniques, i.e. the locus-specific probes (LSI) method and the whole chromosome painting (WCP) technique. RESULTS: The frequency of normal or balanced sperm resulting from alternate meiotic segregation was 86%. Incidences of unbalanced complements resulting from adjacent segregation modes were 12.79% and 14.36% in LSI and WCP assays, respectively. No significant excess of nullisomy or disomy for the affected chromosomes was observed. CONCLUSIONS: Similar results in segregation were obtained with the two techniques, demonstrating the efficiency of the two strategies for the direct segregation analysis of Roberstsonian translocations. The results obtained indicated a moderate meiotic production of imbalance. This study shows that the rare Robertsonian translocation (13;22) displays a similar distribution of balanced and unbalanced sperm patterns as the common Robertsonian translocations previously studied. This suggests that the behaviour of acrocentric chromosomes was similar in all cases of centric fusion.     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver‐Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver‐Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well‐recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved. © 2002 Wiley‐Liss, Inc.     

Familial reciprocal translocation t(7;16) associated with maternal uniparental disomy 7 in a Silver-Russell patient

We present the case of a maternal heterodisomy for chromosome 7 in the daughter of a t(7;16)(q21;q24) reciprocal translocation carrier. The proband was referred to the hospital for growth retardation and minor facial dysmorphism without mental retardation. A diagnosis of Silver-Russell syndrome was suspected. Chromosomal analysis documented a 46,XX,t(7;16)(q21;q24)mat chromosome pattern. Microsatellite analysis showed a normal biparental inheritance of chromosome 16 but a maternal heterodisomy of chromosome 7. Occurrence of uniparental disomy (UPD) is a well-recognized consequence of chromosomal abnormalities that increase the rate of meiotic nondisjunction, mainly Robertsonian translocations and supernumerary chromosomes. Although reciprocal translocations should, theoretically, be also at increased risk of UPD, only three cases have been reported so far. However, because the association between uniparental disomy and reciprocal translocation may exist with an underestimated frequency, prenatal diagnosis is recommended when clinically relevant chromosomes for UPD are involved.     

Possible interchromosomal effect in embryos generated by gametes from translocation carriers

BACKGROUND: The incidence of abnormal pregnancies in carriers of balanced translocations depends strictly on the chromosomes involved in the translocations. The aim of this study was to verify whether conventional aneuploidy screening could be advantageously combined with preimplantation genetic diagnosis (PGD) for translocations. METHODS: Twenty-eight carriers of Robertsonian and reciprocal translocations underwent 43 PGD cycles; specific probes were used to screen the translocation in 172 embryos generated by 35 cycles; most of these embryos were also screened for chromosomes 13, 16, 18, 21, 22 (n = 166), XY (n = 107), 1 (n = 17) and 15 (n = 88). For the remaining eight cycles (carriers of reciprocal translocations) only the chromosomes involved in common aneuploidy screening were investigated on the 40 embryos generated in vitro. RESULTS: In Robertsonian translocations, the proportion of embryos with abnormalities due to the translocation was 21%, common aneuploidies contributed 31% of total abnormalities, whereas the remaining 36% of embryos had abnormalities due to both types of chromosome. For reciprocal translocations, the chromosomes involved in the translocation were responsible for 65% of total abnormalities; only 6% of the embryos were abnormal for common aneuploidies and 16% carried abnormalities due to both the chromosomes involved in the translocation and those not related to the translocation. CONCLUSIONS: An interchromosomal effect seems to play a role in the case of Robertsonian translocations, where the relevant contribution of aneuploidy exposes the couple to an additional risk of abnormal pregnancy.     

Investigation of two cases of paternal disomy 13 suggests timing of isochromosome formation and mechanisms leading to uniparental disomy

Uniparental disomy (UPD) is the abnormal inheritance of two copies of a chromosome from the same parent. Possible mechanisms for UPD include trisomy rescue, monosomy rescue, gametic complementation, and somatic recombination. Most of these mechanisms can involve rearranged chromosomes, particularly isochromosomes and Robertsonian translocations. Both maternal and paternal UPD have been reported for most of the acrocentric chromosomes. However, only UPD for chromosomes 14 and 15 show an apparent imprinting effect. Herein, we present two cases of paternal UPD 13 involving isochromosomes. Both cases were referred for UPD studies due to the formation of a de novo rea(13q13q). Case 2 was complicated by the segregation of a familial rob(13q14q) of maternal origin. Both propositi were phenotypically normal at the time of examination. Polymorphic marker analysis in Case 1 showed the distribution of alleles of markers along chromosome 13 to be complete isodisomy, consistent with an isochromosome. This rearrangement could have occurred either meiotically, without recombination, or mitotically. A likely mechanism for UPD in this case is monosomy rescue, through postzygotic formation of the isochromosome. In Case 2 the distribution of proximal alleles indicated an isochromosome, but recombination was evident. Thus, this isochromosome must have formed prior to or during meiosis I. A likely mechanism for UPD in this case is gametic complementation, since the mother carries a rob(13q14q) and is at risk of producing aneuploid gametes. However, trisomy rescue of a trisomy 13 conceptus cannot be completely excluded. Given that both cases were phenotypically normal, these data further support that paternal UPD 13 does not have an adverse phenotypic outcome and, thus, does not show an apparent imprinting effect.     

The contribution of uniparental disomy to congenital development defects in children born to mothers at advanced childbearing age

Most instances of maternal uniparental disomy (UPD) start as trisomies and, similar to the latter, show a significant increase of mean maternal age at delivery. To investigate the incidence of UPD in offspring of older mothers, we investigated two groups of patients: 1) 50 patients with unclassified developmental defects born to mothers 35 years or older at delivery were tested for UPD for all autosomes by means of microsatellite marker analysis; 2) The incidence of UPD versus other etiologies in correlation, with maternal age below versus 35 years and above at delivery was studied in patients investigated in our laboratory for maternal UPD 15 (Prader-Willi syndrome, PWS), paternal UPD 15 (Angelman syndrome, AS), and maternal UPD 7 (Silver-Russell syndrome, SRS). In group 1, four patients of 50 showed UPD for an autosome that clarified the etiology of their developmental problems: a 27-year-old woman with growth retardation and early puberty disclosed maternal heterodisomy 14; a 15-year-old girl revealed paternal isodisomy 15; a 6-year-old boy with suspected Smith-Lemli-Opitz syndrome was shown to have maternal heterodisomy 16 with additional mosaic partial trisomy 16(pter-p13); a 16-month-old girl with intrauterine growth retardation and a dysmorphic pattern revealed maternal heterodisomy 7. In group 2 the offspring of older mothers showed a clear increase of UPD compared with the mothers below 35 years at delivery. The binomial distribution gave P-values of 1.9 x 10(-10), 2.6 x 10(-4), and 0.01 for PWS, AS, and SRS, respectively. The correlation between increase of paternal UPD 15 with advanced maternal age might be explained by maternal non-disjunction leading to hypohaploid gamete (nullisomy) for chromosome 15 with subsequent or concomitant duplication of the paternal homologue (paternal isodisomy). The three UPD 15 AS cases with mothers older than 35 years at delivery revealed isodisomy, whereas the three cases from younger mothers showed heterodisomy. This study confirms the hypothesis that uniparental disomy is a not negligible cause of congenital developmental anomalies in children of older mothers.     

An acquired Robertsonian translocation in prolymphocytic leukemia: a case presentation and review

Robertsonian translocations between the acrocentric autosomes are the most common type of constitutional chromosome rearrangement in humans. However, Robertsonian translocations are very rarely acquired in cancer cells. We report a patient with prolymphocytic leukemia and an acquired Robertsonian translocation in the leukemic cells. The translocation was between chromosomes #13 and #15; t(13;15)(q11;p12). Two other cases of malignancy with an acquired Robertsonian translocation have been found, one being of the t(13;15) type, which accounts for only 1% of constitutional Robertsonian translocations. We propose, therefore, that although Robertsonian translocations are occasionally observed in cancer cells, they are very rarely acquired.     

Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13)

Behnecke A, Hinderhofer K, Jauch A, Janssen JWG, Moog U. Silver-Russell syndrome due to maternal uniparental disomy 7 and a familial reciprocal translocation t(7;13). Silver-Russell syndrome (SRS) is a genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation, typical facial features and a spectrum of additional features including body and limb asymmetry and clinodactyly. Maternal uniparental disomy for chromosome 7 (upd(7)mat) was shown to occur in 5-10% of patients with SRS. Maternal UPD7 is clinically often associated with mild SRS. Parents of an affected child are given a negligible recurrence risk as all reported cases with upd(7)mat have been sporadic so far. In general, chromosomal rearrangements-like translocations increase the likelihood of uniparental disomy (UPD) for the chromosomes involved. However, SRS as the result of a upd(7)mat in association with an inherited chromosomal translocation involving chromosome 7 has only been reported once before. Here, we describe the second case of SRS with upd(7)mat due to a familial reciprocal translocation t(7;13). This emphasizes the importance of chromosome analysis in SRS patients with upd(7)mat to rule out chromosomal rearrangements despite their rare occurrence as they are of great relevance for genetic counseling of SRS families.     

A rapid microarray based whole genome analysis for detection of uniparental disomy

To date, uniparental disomy (UPD) with phenotypic relevance is described for different chromosomes and it is likely that additional as yet unidentified UPD phenotypes exist. Due to technical difficulties and limitations of time and resources, molecular analyses for UPD using microsatellite markers are only performed in cases with specific phenotypic features. In this study, we carried out a whole genome UPD screening based on a microarray genotyping technique. Six patients with the diagnosis of both complete or segmental UPD including Prader-Willi syndrome (PWS; matUPD15), Angelman syndrome (AS; patUPD15), Silver-Russell syndrome (SRS; matUPD7), Beckwith-Wiedemann syndrome (BWS; patUPD11p), pseudohypoparathyroidism (PHP; patUPD20q) and a rare chromosomal rearrangement (patUPD2p, matUPD2q), were genotyped using the GeneChip Human Mapping 10K Array. Our results demonstrate the presence of UPD in the patients with high efficiency and reveal clues about the mechanisms of UPD formation. We thus conclude that array based SNP genotyping is a fast, cost-effective, and reliable approach for whole genome UPD screening.     

Advanced parental age in maternal uniparental disomy (UPD): implications for the mechanism of formation

Uniparental disomy (UPD) describes the inheritance of a pair of chromosomes from only one parent. Meiotic nondisjunction followed by trisomy rescue is considered to be the major mechanism of formation. A literature search for cases with whole chromosome UPD other than UPD 15 was performed. Information on parental age was available in 111 cases with maternal UPD and in 34 cases with paternal UPD. In 52 out of 74 cases with maternal heterodisomy, information on the time of nondisjunction was also available. Around two-thirds of these cases were due to a maternal meiosis I error. Compared with the mean maternal age of 30.0 years in Bavarian mothers, in the year 2000 an advanced mean maternal age of 34.8 years was found in cases with maternal heterodisomy (n=74; P<0.0001). Almost no difference in the mean maternal age was observed between meiosis I errors (35.56 years; n=30) and meiosis II errors (35.78 years; n=14). The mean maternal age was 31.46 years in cases with maternal isodisomy and a normal karyotype (n=24), and the mean paternal age was 31.48 years in cases with paternal isodisomy (n=28). The various mean parental ages in heterodisomic and isodisomic cases are considered to reflect strongly the different mechanisms of formation: trisomy rescue or gamete complementation, which implies a meiotic nondisjunction in maternal heterodisomic UPD, and postzygotic somatic reduplication in cases with paternal and maternal isodisomic UPD.     

Acquired Robertsonian translocations are not rare events in acute leukemia and lymphoma

Robertsonian translocations are the most common constitutional structural abnormalities but are rarely reported as acquired aberrations in hematologic malignancies. The nonhomologous acrocentric rearrangements are designated as Robertsonian translocations, whereas the homologous acrocentric rearrangements are referred to as isochromosomes. Robertsonian rearrangements have the highest mutation rates of structural chromosome rearrangements based on surveys of newborns and spontaneous abortions. It would be expected that Robertsonian recombinations would be more common than suggested by the literature. A survey of the cytogenetics database from a single institution found 17 patients with acquired Robertsonian rearrangement and hematologic malignancies. This is combined with data from the literature for a total of 237 patients. All of the possible types of Robertsonian rearrangements have been reported in hematologic malignancies, with the i(13q), i(14q), and i(21q) accounting for nearly 60%. Complex karyotypic changes are seen in the majority of cases, corresponding with disease evolution. These karyotypes consistently show loss of chromosomes 5 and/or 7 in the myelocytic disorders, nonacrocentric isochromosomes, and centromeric breakage and reunion. However, nearly 25% of the acquired rearrangements were found as the sole abnormality or in addition to an established cytogenetic aberration. Most of these were the i(14q) with the myelodysplasia subtypes refractory anemia and chronic myelomonocytic leukemia.     

47,XX,UPD(7)mat,+r(7)pat/46,XX,UPD(7)mat mosaicism in a girl with Silver-Russell syndrome (SRS): possible exclusion of the putative SRS gene from a 7p13-q11 region

Maternal uniparental disomy for chromosome 7 (UPD7) may present with a characteristic phenotype reminiscent of Silver-Russell syndrome (SRS). Previous studies have suggested that approximately 10% of SRS patients have maternal UPD7. We describe a girl with a mos47,XX,+mar/46,XX karyotype associated with the features of SRS. Chromosome painting using a chromosome 7 specific probe pool showed that the small marker was a ring chromosome 7 (r(7)). PCR based microsatellite marker analysis of the patient detected only one maternal allele at each of 16 telomeric loci examined on chromosome 7, but showed both paternal and maternal alleles at four centromeric loci. Considering her mosaic karyotype composed ofdiploid cells and cells with partial trisomy for 7p13-q11, the allele types obtained at the telomeric loci may reflect the transmission of one maternal allele in duplicate, that is, maternal UPD7 (complete isodisomy or homodisomy 7), whereas those at the centromeric loci were consistent with biparental contribution to the trisomic region. It is most likely that the patient originated in a 46,XX,r(7) zygote, followed by duplication of the maternally derived whole chromosome 7 in an early mitosis, and subsequent loss of the paternally derived ring chromosome 7 in a subset of somatic cells. The cell with 46,XX,r(7) did not survive thereafter because of the monosomy for most of chromosome 7. If the putative SRS gene is imprinted, it can be ruled out from the 7p11-q11 region, because biparental alleles contribute to the region in our patient.